Unruptured Cerebral Aneurysms in Elderly Patients

Transcription

1 REVIEW ARTICLE Neurol Med Chir (Tokyo) 57, , 2017 doi: /nmc.ra Online April 19, 2017 Unruptured Cerebral Aneurysms in Elderly Patients Tomohito Hishikawa, 1 and Isao Date 1 1 Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan Abstract The prevalence of unruptured cerebral aneurysms (UCAs) in elderly patients is increasing in our aging population. UCA management in elderly patients has some difficulties, such as reduced life expectancy, increased comorbidities and treatment risks, and poor prognosis in case of rupture. In this review article, we summarize the most recent findings on the natural history, therapeutic options and treatment results for UCAs exclusively in elderly patients, and describe possible medical treatments for patients with UCAs. Key words: elderly, natural history, treatment, unruptured cerebral aneurysm, outcome Introduction The global population is currently aging at an accelerating pace. In developed countries, more than 75% of people die after 75 years of age, and in Japan, which has the longest life expectancy, female life expectancy was 86 years in ) The advancement and prevalence of neuroimaging modalities, such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA), and a prolonged average life expectancy have led to increased detection of unruptured cerebral aneurysms (UCAs) in Japan. The Unruptured Cerebral Aneurysm Study of Japan (UCAS Japan) included a total of 5,720 patients and 1,577 patients (28%) were over 70 years of age. 2) Elderly patients with UCAs have some intrinsic difficulties, such as decreased life expectancy, increased presence of comorbid disease, increased surgical treatment risks, and poor prognosis for elderly patients with ruptured aneurysms. 3) In this article, we review the natural history of UCAs in elderly patients, surgical results of UCAs in elderly patients, and feasibility of medical treatment for patients with UCAs. Natural History of UCAs in Elderly Patients Prevalence of UCAs Iwamoto et al. evaluated 1230 consecutive autopsy cases from 1962 to 1991 in the Hisayama study and they reported that the prevalence of UCAs was Received November 23, 2016; Accepted February 4, %. 4) They demonstrated that the prevalence of UCAs increased with age and that it was highest in patients 80 years of age or older (4.8%). 4) Harada et al. revealed that the prevalence of UCAs detected by MRA was 3.2% and it increased with age in both sexes in 8696 healthy asymptomatic Japanese adults from 2010 to ) However, a meta-analysis for prevalence of UCAs showed that the prevalence was lower in patients younger than 30 years of age, but not in patients aged years, years, years, years, and years compared with patients aged 80 years or older (prevalence 3.0%). 6) The influence of age on the prevalence of UCAs remains controversial. Risk factors for UCA rupture The natural history of UCAs in the general populations was reported in large prospective studies. 2,7 11) The International Study of Unruptured Intracranial Aneurysms (ISUIA) indicated that the size (7 mm or larger) and location (tip of basilar arteries, internal carotid-posterior communicating arteries [IC-PComA]) were significant risk factors for rupture. 7) UCAS Japan showed that the annual rate of rupture was 0.95% and that UCAs larger than 7 mm, located in the anterior communicating and IC-PComA, and with a daughter sac had independent risk factors for rupture in the general population. 2) It is unclear whether the natural history of UCAs in the general population is the same as that in elderly patients. Clarifying the natural history of UCAs in elderly patients has an important role when considering therapeutic strategies in a clinical setting. Hishikawa et al. 247

2 248 T. Hishikawa et al. performed a pooled analysis of prospective cohorts using three studies (UCAS Japan, UCAS II, and the study at the Jikei University School of Medicine), all of which were representative of largescale studies performed in Japan to identify risk factors for UCA rupture in elderly patients 70 years of age or older. 12) A total of 1896 patients with 2227 UCAs were evaluated during a mean follow-up period of days, and the annual rupture rate was reported to be 1.6% (68 subarachnoid hemorrhages/4167 patient-years) in the study. 12) Additionally, it was demonstrated that the cumulative rates of rupture in patients older than 80 years of age were significantly higher than in those of patients aged years. 12) In patients aged 80 years or older, aneurysms 7 mm or larger and IC-PComA aneurysms were the independent predictors for UCA rupture in elderly patients. 12) The larger aneurysms are a common risk factor for UCA rupture in the general population and elderly patients. Aneurysm size was significantly related to patients age in the UCAS Japan, which may be one possible explanation for the higher annual rupture rate in elderly patients. 2) The UCAS Japan showed that elderly patients had significantly more posteriorly located aneurysms, and only IC-PComA aneurysms remain an independent risk for rupture in elderly patients, probably because of the difference in the distribution of aneurysms regarding location and age. 2,12) The investigation by Hishikawa et al. identified some important findings and problems, such as a higher rupture rate in elderly patients, and a significant risk factor for rupture in patients aged 80 years or older. The annual rupture rate of UCAs in elderly patients is higher than that reported in the general Japanese population and non-japanese populations. 2,7,9,11,12) Wermer et al. reported that increased age was one of the risk factors for UCA rupture, 13) while some studies demonstrated that age was inversely related to UCA rupture. 9,11) It is unclear how age itself relates to the biological mechanisms of UCA rupture. Table 1 shows a summary of the annual rupture rate and risk factors for UCA rupture in large cohort studies. It is noteworthy that the only report by Hishikawa et al. exclusively included elderly patients in their investigation; however, this study had several limitations. First, the difference in the frequency of surgical intervention among patients aged years (28%) and patients aged 80 years or older (4%) may have been due to age bias. Second, comorbid diseases were not evaluated in this study. To assess the natural history of UCAs in elderly patients more accurately, it would be meaningful to evaluate the influence of comorbid diseases, such as hyperlipidemia, diabetes mellitus, polycystic kidney disease, cerebral infarction, ischemic heart disease, and malignant tumor, on the risk of UCA rupture in further studies. Therapeutic Options for UCAs in Elderly Patients Comparison between surgical clipping and coil embolization Repairing the UCAs in elderly patients involves selecting between surgical clipping and coil embolization, and the best option remains controversial because there is no randomized clinical trial (RCT) for UCAs. The International Subarachnoid Aneurysm Trial (ISAT) is an RCT that was undertaken to compare the safety and efficacy of coil embolization with surgical clipping in subarachnoid hemorrhage (SAH) patients for whom it was safe to undergo either treatments. 14) According to the ISAT subgroup analysis of 278 SAH elderly patients who were 65 years or older, coil embolization should probably be the favored treatment of a ruptured internal carotid artery (ICA) and IC-PComA aneurysms, whereas surgical clipping should be the treatment of choice for ruptured middle cerebral artery aneurysms. 15) However, these results cannot be simply applied to the UCAs in elderly patients because there are some differences in the natural history and aneurysm characteristics between ruptured aneurysms and UCAs. In the absence of an RCT comparing these two surgical modalities, data based on non-rcts should be used to decide on therapeutic options for elderly patients with UCAs. Some retrospective and prospective cohort studies have compared the outcomes in elderly patients with UCAs, who were treated using surgical clipping with those who were treated using coil embolization ) Mahaney et al. reported that poor neurological outcome from aneurysm- or procedure-related morbidity and mortality was significantly higher in the surgical group for patients older than 65 years of age: 19.0%, compared with 8.0% in the endovascular group in the subanalysis of 4059 patients in ISUIA. 20) Bekelis et al. revealed that there was no difference between coil embolization and surgical clipping for 1-year postoperative mortality or 90-day readmission rate, but surgical clipping was associated with a higher rate of discharge to a rehabilitation facility and a longer length of stay for elderly patients. 22) The study of the National Inpatient Sample in the United States showed that patients years of age who underwent coil embolization had significantly lower morbidity (6.9% versus 26.8%) and mortality (0.8% versus 2.0%)

3 UCAs in Elderly Patients 249 Table 1 Annual rupture rates and risk factors for UCA rupture in large cohort studies Study and year of publication Country Inclusion criteria No. of patients No. of aneurysms FU durations (mean) Age (years) (mean ± SD) Aneurysm size (mm) (mean ± SD) Annual rupture rate (%) Risk factors for UCA rupture ISUIA, 7) 2003 USA, Canada, and Europe General population, 2 mm Ishibashi, et al., 8) 2009 Japan General population SUAVe study, 9) 2010 Japan General population, <5 mm UCAS Japan, 2) 2012 Japan General population, 3 mm Juvela, et al., 11) 2013 Finland General population Hishikawa, et al., 12) 2015 Japan Elderly patients (>70 years) years 55.2 ± ± mm, BA tip, IC-PComA days months days years days 60.8 ± ± History of SAH, 10 mm, Posterior circulation 61.9 ± ± <50 yrs, Hypertension, 4 mm, Multiplicity 62.5 ± ± mm, AComA, IC-PComA, Irregular shape 41.8 ± ± Age inversely related, Smoking, 7 mm, AComA 74.3 ± ± >80 years, 7 mm, IC-PComA AComA: anterior communicating artery, BA: basilar artery, FU: follow-up, IC-PComA: internal carotid-posterior communicating artery, ISUIA: International Study of Unruptured Intracranial Aneurysms, SAH: subarachnoid hemorrhage, SD: standard deviation, SUAVe: Small Unruptured Intracranial Aneurysm Verification, UCAs: unruptured cerebral aneurysms, UCAS: Unruptured Cerebral Aneurysm Study.

4 250 T. Hishikawa et al. compared with patients who underwent clipping, and that patients aged 80 years or older who were treated by coil embolization also had significantly lower morbidity (9.8% versus 33.5%) and mortality (2.4% versus 21.4%) compared with patients treated using surgical clipping. 18) In this study, only 15% of patients aged 80 years or older were treated by surgical clipping and the morbidity and mortality rates for these patients were extremely high. This was probably because these cases were considered not to be amenable to coil embolization and were at high risk for treatment complications. According to the meta-analysis of elderly patients who underwent coil embolization to treat UCAs, the perioperative stroke and mortality rate was 4% and 1%, respectively, and the rate of good clinical outcome at 1 year was 93%. 23) These data indicate that coil embolization may be the best option to treat UCAs in elderly patients. There are some explanations for worse outcomes of surgical clipping for UCAs in elderly patients. First, perioperative stroke in surgical clipping was directly associated with worse outcomes in elderly patients. 20) Second, increased pain and slower mobilization as a result of surgical clipping, which is a more invasive procedure, may lead to more secondary medical complication in elderly patients. 22) The retrospective studies comparing surgical clipping and coil embolization have some important limitations in interpreting the results. First, these studies are retrospective and patients were not randomized to treatment. Therefore, there is a significant potential for selection bias that might have affected the outcomes of surgical clipping or coil embolization. 18) Second, the findings from these studies are based on a specific population of elderly patients with UCAs, and these findings may not be generalizable to other populations. 22) RCTs comparing surgical clipping, coil embolization, and observation in different population are necessary to decide upon an evidence-based therapeutic management plan for elderly patients with UCAs. Flow diverters for UCAs in elderly patients Flow diverters are recently developed endovascular devices for complex aneurysms. The meta-analysis including 29 studies showed that treatment with flow diverters was feasible and effective with high complete occlusion rates. 24) Recently, flow diverter devices Pipeline Flex (Medtronic), was introduced in Japan, and this device can be used for proximal ICA aneurysms larger than 10 mm. In the future, the number of elderly patients undergoing aneurysm embolization with a flow diverter is expected to increase. The outcomes of elderly patients with UCAs that are treated using flow diverters should be elucidated because the mechanisms by which flow diverters repair UCAs are different from those of coil embolization. Brinjikji et al. reported that the overall complication rates for the Pipeline Embolization Device (PED) treatment in highly selected elderly patients, 70 years of age or older were acceptably low and concluded that age alone should not be considered an exclusion criteria when PED treatment is considered. 25) Indication for treatment of UCAs in elderly patients When deciding whether to treat or observe UCAs in elderly patients, several factors must be considered, such as precise knowledge of natural history, treatment-related risks, the individual s comorbid diseases and life expectancy, and the wishes of the patients and their families. Indication for the treatment of UCAs in elderly patients should be determined individually. Data based on prospective cohorts identifying risk factors for UCA rupture and non-rcts comparing surgical clipping and coil embolization indicate that elderly patients with aneurysms 7 mm or larger, or those with IC-PComA aneurysms may be candidates for coil embolization if they are considered to be amenable to safe coil embolization. Potential medical treatment for UCAs Cerebral aneurysm formation involves endothelial dysfunction, a mounting inflammatory response, vascular smooth muscle cell phenotypic modulation, extracellular matrix remodeling, and subsequent cell death and vessel wall degradation. 26) It has also been reported that dental infection caused by endodontic and periodontal bacteria may contribute to the pathophysiology of ruptured cerebral aneurysms. 27) Recent studies have shown that chronic inflammation plays a role in the development or rupture of cerebral aneurysms and experimental therapies targeting different molecular inflammatory effectors in animal models were shown to be efficacious and promising ) If clinical evidence that anti-inflammatory drugs prevent UCAs from bleeding or growing is provided, medical treatment for elderly patients with UCAs could be the firstline therapy. In this section, we introduce some anti-inflammatory drugs for cerebral aneurysms that were used in experimental studies. Statins Statins have anti-inflammatory effects in various vascular diseases. Some types of statins have been experimentally investigated and reported to have

5 UCAs in Elderly Patients 251 protective effects on the cerebral aneurysm formation and progression. 28,29,31) Aoki et al. demonstrated that pitavastatin had a suppressive effect on cerebral aneurysm progression through the inhibition of nuclear factor-κb activation in the aneurysm walls in a rat model. 29) In Japan, a multi-center prospective randomized trial called Small Unruptured Aneurysm Verification-Prevention Effect against Growth of cerebral Aneurysm Study Using Statins (SUAVe-PEGASUS) is currently ongoing. This study is evaluating whether statins have protective effects on human UCAs. Aspirin Hasan et al. performed a subanalysis of 271 subjects enrolled into ISUIA, and they showed that patients with UCAs who used aspirin three times weekly to daily had a significantly lower risk of rupture compared with those who had never taken aspirin. 32) They expected that aspirin may potentially be a therapeutic agent to prevent cerebral aneurysm growth and rupture by inhibiting several inflammatory mediators. 32) Free radical scavenger (Edaravone) Aoki et al. demonstrated that oral intake of edaravone in a rat model of cerebral aneurysms effectively inhibited reactive oxygen species and medial degradation in the aneurysm wall, which suggests that edaravone has a protective effect against rupture. 30) Edaravone is widely used for patients with acute cerebral infarction in Japan, and it is feasible options for UCA. Tetracycline derivatives Makino et al. demonstrated that tetracycline derivatives (doxycycline and minocycline) reduced the incidence of aneurysmal rupture through their general anti-inflammatory effects in a mouse model of intracranial aneurysm. 33) Conclusions We reviewed recent findings on the natural history, therapeutic options, and treatment results of UCAs in elderly patients and described potential medical treatments for UCAs, based on experimental studies. We expect that this article will help clinicians to decide the therapeutic strategy for UCAs in elderly patients in a clinical setting. Conflicts of Interest Disclosure All authors who are a member of the Japan Neurosurgical Society (JNS) have registered online self-reported COI Disclosure Statement Forms through the website. The authors have no interests to declare. References 1) Lunenfeld B, Stratton P: The clinical consequences of an ageing world and preventive strategies. Best Pract Res Clin Obstet Gynaecol 27: , ) Morita A, Kirino T, Hashi K, Aoki N, Fukuhara S, Hashimoto N, Nakayama T, Sakai M, Teramoto A, Tominari S, Yoshimoto T; UCAS Japan investigators: The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 366: , ) Hishikawa T, Takasugi Y, Shimizu T, Haruma J, Hiramatsu M, Tokunaga K, Sugiu K, Date I: Cerebral vasospasm in patients over 80 years treated by coil embolization for ruptured cerebral aneurysms. Biomed Res Int 2014: , ) Iwamoto H, Kiyohara Y, Fujishima M, Kato I, Nakayama K, Sueishi K, Tsuneyoshi M: Prevalence of intracranial saccular aneurysms in a Japanese community based on a consecutive autopsy series during 30-year observational period. The Hisayama study. Stroke 30: , ) Harada K, Fukuyama K, Shirouzu T, Ichinose M, Fujimura H, Kakumoto K, Yamanaga Y: Prevalence of unruptured intracranial aneurysms in healthy asymptomatic Japanese adults: differences in gender and age. Acta Neurochir 155: , ) Vlak MH, Algra A, Brandenburg R, Rinkel GJ: Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and metaanalysis. Lancet Neurol 10: , ) Wiebers DO, Whisnant JP, Huston J, Meissner I, Brown RD Jr, Piepgras DG, Forbes GC, Thielen K, Nichols D, O Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC; International Study of Unruptured Intracranial Aneurysms investigators: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362: , ) Ishibashi T, Murayama Y, Urashima M, Saguchi T, Ebara M, Arakawa H, Irie K, Takao H, Abe T: Unruptured intracranial aneurysms: Incidence of rupture and risk factors. Stroke 40: , ) Sonobe M, Yamazaki T, Yonekawa M, Kikuchi H: Small unruptured intracranial aneurysm verification study. SUAVe study, Japan. Stroke 41: , ) Morita A and UCAS II Study Group. Management outcomes in the Unruptured Cerebral Aneurysm Study II (UCAS II): Interim report Quest for standards and current status in Japan. Jpn J Neurosurg (Tokyo) 20: , ) Juvela S, Poussa K, Lehto H, Porras M: Natural history of unruptured intracranial aneurysms.

6 252 T. Hishikawa et al. A long-term follow-up study. Stroke 44: , ) Hishikawa T, Date I, Tokunaga K, Tominari S, Nozaki K, Shiokawa Y, Houkin K, Murayama Y, Ishibashi T, Takao H, Kimura T, Nakayama T, Morita A; UCAS Japan and UCAS II investigators: Risk of rupture of unruptured cerebral aneurysms in elderly patients. Neurology 85: , ) Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ: Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristcs: an updated meta-analysis. Stroke 38: , ) Molyneux AJ, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R: International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Lancet 360: , ) Ryttlefors M, Enblad P, Kerr RS, Molyneux AJ: International subarachnoid aneurysm trial of neurosurgical clipping versus endovascular coiling. Subgroup analysis of 278 elderly patients. Stroke 39: , ) Barker FG, Amin-Hanjani S, Butler WE, Hoh BL, Rabinov JD, Pryor JC, Oglivy CS, Carter BS: Agedependent differences in short-term outcome after surgical or endovascular treatment of unruptured intracranial aneurysms in the United States, Neurosurgery 54: 18 30, ) Alshekhlee A, Mehta S, Edgell RC, Vora N, Feen E, Mohammadi A, Kale SP, Cruz-Flores S: Hospital mortality and complication of electively clipped or coiled unruptured intracranial aneurysm. Stroke 41: , ) Brinjikji W, Rabinstein AA, Lanzino G, Kallmes D, Cloft HJ: Effect of age on outcomes of treatment of unruptured cerebral aneurysms: a study of the National Inpatient Sample Stroke 42: , ) Jang EW, Jung JY, Hong CK, Joo JY: Benefits of surgical treatment for unruptured intracranial aneurysms in elderly patients. J Korean Neurosurg Soc 49: 20 25, ) Mahaney KB, Brown Jr RD, Meissner I, Piepgras DG, Huston J, Zhang J, Torner JC; ISUIA investigators: Age-related differences in unruptured intracranial aneurysms: 1-year outcomes. J Neurosurg 121: , ) Qureshi AI, Chaudhry SA, Tekle WG, Suri MF: Comparison of long-term outcomes associated with endovascular treatment vs surgical treatment among medicare beneficiaries with unruptured intracranial aneurysms. Neurosurgery 75: , ) Bekelis K, Gottlieb DJ, Su Y, O Malley AJ, Labropoulos N, Goodney P, Lawton MT, MacKenzie TA: Comparison of clipping and coiling in elderly patients with unruptured cerebral aneurysms. J Neurosurg May 20: 1 8, 2016 [Epub ahead of print] 23) Sturiale CL, Brinjikji W, Murad MH, Lanzino G: Endovascular treatment of intracranial aneurysms in elderly patients: a systematic review and metaanalysis. Stroke 44: , ) Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF: Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke 44: , ) Brinjikji W, Kallmes DF, Cloft HJ, Lanzino G: Agerelated outcomes following intracranial aneurysm treatment with the Pipeline Embolization Device: A subgroup analysis of the IntrePED registry. J Neurosurg 124: , ) Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS: Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab 32: , ) Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Öhman JE: The connection between ruptured cerebral aneurysms and odontogenic bacteria. J Neurol Neurosurg Psychiatry 84: , ) Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N: Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 39: , ) Aoki T, Kataoka H, Ishibashi R, Nakagami H, Nozaki K, Morishita R, Hashimoto N: Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor κb pathway. Neurosurgery 64: , ) Aoki T, Nishimura M, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N: Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox(-/-) mice. Lab Invest 89: , ) Kimura N, Shimizu H, Eldawoody H, Nakayama T, Saito A, Tominaga T, Takahashi A: Effect of olmesartan and pravastatin on experimental cerebral aneurysms in rats. Brain Res 1322: , ) Hasan DM, Mahaney KB, Brown Jr RD, Meissner I, Piepgras DG, Huston J, Capuano AW, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators: Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 42: , ) Makino H, Tada Y, Wada K, Liang EI, Chang M, Mobashery S, Kanematsu Y, Kurihara C, Palova E, Kanematsu M, Kitazato K, Hashimoto T: Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke 43: , 2012 Address reprint requests to: Tomohito Hishikawa, MD, Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Okayama , Japan. t-hishi@md.okayama-u.ac.jp